LIGAND PHARMACOLOGY OF ESTROGEN RECEPTORS

雌激素受体的配体药理学

• 批准号: 6381790
• 负责人: THOMAS Sterling SCANLAN
• 金额: $ 28.11万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6381790
• 关键词: chemical structure function; estrogen analog; estrogen inhibitor; estrogen receptors; genetic regulation; genetic regulatory element; hormone regulation /control mechanism; ligands; pharmacogenetics; pharmacokinetics; protein isoforms; receptor binding; receptor expression

The long-term objective of this project is to develop a molecular-level understanding of the tissue selectivity of ligands that modulate the estrogen receptors (ERalpha and ERbeta). Drugs that target estrogen signaling pathways such as tamoxifen and raloxifene display antiestrogenic effects in certain tissues ans estrogenic effects in other tissues. Understanding the molecular basis of this tissue selectivity will be useful for designing safer and more effective-based therapeutics. The proposed experiments are designed to test the hypothesis that ER ligand pharmacology derives from the interplay of three parameters: ligand structure, receptor subtype (ERalpha and ERbeta), and the type of response element in the promoter of a given gene that is the site of regultion by the ER. The ER/AP-1 site is a response element where differential ligand activation profiles are observed for ERalpha and ERbeta. The specific aim is to map the regions of ERalpha and ERbeta that mediate this differential ligand activation. The second specific aim of the project is to probe the structural differences between raloxifene and tamoxifen to identify the chemical substructures of these drugs that correlate with the differences observed in ligand activation at an R/Ap-1 site. The ER/AP-1 assay that facilitated discovery of the differential ligand activation properties of ERalpha and ERbeta is an artificial cellular transcription assay that uses a test promoter driving transcription of a reporter gene. There is great interest now to ask whether endogenous in target tissues can be regulated in a similar way; i.e. in an ERbeta expressing tissue which genes are up-regulated by antiestrogens such as tamoxifen and raloxifene and down-regulated by estradiol? This question is addressed in specific aim 3 through experiments using differential gene expression array technology. The endogenous estrogen-regulated genes that are discovered with this approach will be characterized through experiments described in specific aim 4. In particular, the promoters of these genes will be analyzed to identify the type of response element that facilitates regulation through the ER.

该项目的长期目标是从分子水平了解调节雌激素受体（ER α和ER β）的配体的组织选择性。 靶向雌激素信号通路的药物如他莫昔芬和雷洛昔芬在某些组织中显示抗雌激素作用，在其他组织中显示雌激素作用。了解这种组织选择性的分子基础将有助于设计更安全和更有效的治疗方法。 所提出的实验旨在检验ER配体药理学来自三个参数的相互作用的假设：配体结构，受体亚型（ER α和ER β），以及给定基因启动子中的响应元件类型，该基因是ER调节的位点。 ER/AP-1位点是一个反应元件，其中观察到ER α和ER β的不同配体活化特征。 具体的目的是映射区域的ER α和ER β介导这种差异配体激活。 该项目的第二个具体目标是探索雷洛昔芬和他莫昔芬之间的结构差异，以确定这些药物的化学亚结构，这些化学亚结构与在R/Ap-1位点的配体活化中观察到的差异相关。 促进发现ER α和ER β的不同配体活化特性的ER/AP-1测定是一种人工细胞转录测定，其使用驱动报告基因转录的测试启动子。 现在有很大的兴趣问内源性靶组织是否可以以类似的方式调节;即在ER β表达组织中，哪些基因被抗雌激素如他莫昔芬和雷洛昔芬上调，而被雌二醇下调？在具体目标3中，通过使用差异基因表达阵列技术的实验来解决该问题。 用这种方法发现的内源性雌激素调节基因将通过具体目标4中描述的实验来表征。 特别是，这些基因的启动子将进行分析，以确定类型的响应元件，促进通过ER的调节。